title: The first pathogenic mitochondrial methionine tRNA point mutation is discovered in splenic lymphoma.
abstract: We describe a novel point mutation in the mitochondrial DNA transfer RNA methionine gene, a G-to-A transition at position 4450, in a patient with a splenic lymphoma with villous lymphocytes. The patient's lymphocytes were remarkable by the presence of large cytoplasmic inclusions demonstrated as abnormal mitochondria by electron microscopy and led to the discovery of the mutation using denaturing gradient gel electrophoresis as a screening procedure. The pathogenic potential of the mutation was clearly established by the following criteria. It was absent in a control population. It involves a nucleotide that is highly conserved along the phylogenetic tree. The mutation was heteroplasmic and, when present in a high proportion, was associated with morphological alterations of the mitochondria, with defects of respiratory chain complexes activities and with a decrease in the mitochondrially encoded cytochrome c oxidase subunit II. Transfer of the mutation in Rho0 cells allowed to demonstrate its association with a severe respiratory chain dysfunction. However, although the pathogenicity of the mutation was clearly demonstrated, its link with the patient disease remained disputable.
authors.affiliation: INSERM U. 153, 75013 Paris, France.
authors.forename: A
authors.initials: A
authors.lastname: Lombès
authors.forename: D
authors.initials: D
authors.lastname: Bories
authors.forename: E
authors.initials: E
authors.lastname: Girodon
authors.forename: P
authors.initials: P
authors.lastname: Frachon
authors.forename: M M
authors.initials: MM
authors.lastname: Ngo
authors.forename: J
authors.initials: J
authors.lastname: Breton-Gorius
authors.forename: M
authors.initials: M
authors.lastname: Tulliez
authors.forename: M
authors.initials: M
authors.lastname: Goossens
mesh_terms: D000368:Aged; D001483:Base Sequence; D002460:Cell Line; D004252:DNA Mutational Analysis; D004272:DNA, Mitochondrial / Q000737:chemistry / Q000235:genetics; D003576:Electron Transport Complex IV / Q000032:analysis; D006801:Humans; D007150:Immunohistochemistry; D008223:Lymphoma / Q000235:genetics* / Q000473:pathology; D008297:Male; D008928:Mitochondria / Q000201:enzymology / Q000235:genetics*; D018482:Muscle, Skeletal / Q000201:enzymology; D017354:Point Mutation; D012358:RNA, Transfer, Met / Q000235:genetics*; D012689:Sequence Homology, Nucleic Acid; D013160:Splenic Neoplasms / Q000235:genetics* / Q000473:pathology
chemical_list: D004272:DNA, Mitochondrial; D012358:RNA, Transfer, Met; D003576:Electron Transport Complex IV